This investigation is designed to study the neuropathological features of experimentally induced hyperphenylalaninemia. Dendritic alterations in the hippocampus, cerebral cortex and cerebellum of experimentally induced hyperphenylalaninemic rats (PKU model) will be analyzed. Some animals will be made hyperphenylalaninemic in utero by maternal dietary manipulation. Other animals will have induction of hyperphenylalaninemia after birth, by injection while nursing and by diet when weaned. Brains will be processed for routine perikaryal and myelin study, but the major analytical efforts will be directed at detection of abnormalities of dendritic morphology and organization, using the rapid Golgi methods. Preliminary studies suggest dendritic involvement in this PKU model, as well as in human mental retardation syndromes. Neuropathological features of human PKU (i.e., myelin) have not correlated well with the clinical features of mental retardation and seizures. However, no systematic examination of dendrites has been undertaken in this human condition, although dendritic involvement would be clinically suspected. The experimental parameters of this study and future projects are designed to be applicable to some of the major unresolved clinical questions in human PKU, namely: how long PKU patients must remain on the diet; at what age the diet must be started to prevent the neurological consequences of PKU; why children born to treated and untreated mothers with PKU are often microcephalic, small and mentally retarded; and, whether the EEG can be used to predict when the diet can be terminated (cf. Dinker et al, 1979). This model may also prove applicable to investigation of other human diseases of neurological significance, i.e., congenital hypothyroidism.